PROJECT SUMMARY The ability of malignant gliomas to infiltrate remote regions of the brain, far from their primary tumor mass, has continually challenged the development of an effective therapy, and prognosis for patients with these tumors remains poor, with median survival measured in weeks rather than years. Although radiotherapy plays a critical role in extending life for these patients, radiation side effects in CNS can still be devastating and greatly affect quality of life, which prevents the use of higher, cancer-sterilizing doses of radiation to treat the invasive aspects of this disease. This application seeks to demonstrate a new radiobiologic element of particle therapy delivered at ultra-high dose rates, which may reduce normal tissue toxicity in CNS and allow the safe use of higher radiation doses to greater volumes of potentially involved brain, compared to conventional radiotherapies. Recent studies by our group demonstrate the new method is experimentally feasible. We propose to test our new ideas using rodent models of glioma. Furthermore, we will investigate the resulting morphologic, cognitive, and pathologic changes after irradiation to quantify the toxicity of the new method, which we expect to be lower than toxicities of conventional therapies. Collectively, these aims will provide the preclinical data and new biologic knowledge needed to advance therapy towards human clinical trials to improve treatment of malignant glioma and other brain tumors.